1. Field of the Invention
This invention relates to pharmaceutical formulations containing kappa agonist compounds and to their medical use as anti-pruritic agonist at kappa opioid receptors.
2. Reported Developments
A) Antihyperalgesic Kappa Agonists
Opium and its derivatives are potent analgesics that also have other pharmacological effects, and exert their effects by interacting with high-affinity receptors.
It has been shown by investigators that there are at least three major opioid receptor types in the central nervous system (hereinafter CNS) and in the periphery. These receptors, known as mu (.mu.), delta (.delta.) and kappa (.kappa.), have distinct pharmacological profiles, anatomical distributions and functions. [See, for example: Wood, P. L., Neuropharmacology, 21, 487-497, 1982; Simon, E. J., Med. Res. Rev., 11, 357-374, 1991; Lutz et al, J. Recept. Res. 12, 267-286; and Mansour et al, Opioid I, ed. Herz,. A. (Springer, Berlin) pp. 79-106, 1993.] The .delta. receptors are abundant in CNS and mediate analgesia, gastrointestinal motility and various hormonal functions. The .mu. receptors bind morphine-like drugs and mediate the opiate phenomena associated with morphine, including analgesia, opiate dependence, cardiovascular and respiratory functions, and several neuroendocrine effects.
The .kappa. receptors have a wide distribution in CNS and mediate a spectrum of functions including the modulation of drinking, water balance, food intake, gut motility, temperature control and various endocrine functions. They also produce analgesia [See, for example: Leander et al, J. Pharmacol. Exp. Ther. 234, 463-469, 1985; Morley et al, Peptides 4, 797-800, 1983; Manzanares et al, Neuroendocrinology 52, 200-205, 1990; and Iyengar et al, J. Pharmacol. Exp. Ther, 238, 429-436, 1986.]
Most clinically used opioid analgesics such as morphine and codeine act as .mu. receptor agonists. These opioids have well-known, undesirable and potentially dangerous dependence forming side effects. Compounds which are .kappa.-receptor agonists act as analgesics through interaction with .kappa. opioid receptors. The advantage of these agonists over the classical .mu. receptor agonists, such as morphine, lies in their ability to cause analgesia while being devoid of morphine-like behavioral effects and addiction liability.
B) Antihyperalgesic Kappa Agonists as Anti-Pruritic Agents
The prior art has investigated the physiology and treatment of pruritus as illustrated hereunder.
Itch is a well known sensory state associated with the desire to scratch. As with pain, itch can be produced by a variety of chemical, mechanical, thermal or electrical stimuli. In addition to the difference in the sensory quality of itch and pain, they also differ in that (1) itch, unlike pain, can only be evoked from the superficial layers of skin, mucosa, and conjunctiva, and (2) itch and pain usually do not occur simultaneously from the same skin region; in fact, mildly painful stimuli, such as scratching, are effective in eliminating itch. In addition, the application of histamine to skin produces itch but not pain. Itch and pain are further dissociated pharmacologically: itch appears to be insensitive to opiate and non-steroidal anti-inflammatory drug (NSAID) treatment, both of which are effective in treating pain.
Although itch and pain are of a class in that both are modalities of nociception transmitted by small unmyelinated C fibers, evidence that itch is not just a variety of low-threshold pain is overwhelming. Itch leads to the reflex or urge to scratch; pain leads to withdrawal. Removal of the epidermis eliminates itch but causes pain. Analgesics, particularly opiods, relieve pain but often cause itch (see, for example J. Am. Acad. Derm. 24: 309-310, 1991). There can be no doubt that itching is of eminent clinical importance; many systemic and skin diseases are accompanied by persistent or recurrent itch attacks. Current knowledge suggests that itch has several features in common with pain but exhibits intriguing differences as well (see, for example, W. Magerl, IASP Newsletter, pp. 4-7, September/October 1996).
McMahon et al (TINS, Vol. 15, No. 12, pp. 497-501, 1992) provides a description of stimuli (Table a) and a comparison of the established features of itch and pain (Table b):
TABLE a ______________________________________ Stimuli that can elicit or augment itch ______________________________________ Physical Mechanical. Light touch, pressure, suction. Thermal. Warming. Electrical. Focal transcutaneous repetitive stimulation, transcutaneous constant current stimulation, intraneural microstimulation. Chemical Non-specific irritants. Acids, alkalis. Inflammatory mediators. Histamine, kallikrein, bradykinin, prostaglandins. Histamine-releasing substances. Compound 48/80, protamine, C3a. Peptidases. Mucunain, papain, trypsin, mast cell chymase. Neuropeptides. Substance P, vasoactive intestinal polypeptide , neurotensin, secretin. Opioids. Morphine, .beta.-endorphin, enkephalin analogues. ______________________________________
TABLE b ______________________________________ Comparison of the established features of itch and pain ITCH PAIN ______________________________________ Psychophysiology Tissue Skin. Mucous Most tissues membranes Stimulus See Table a Many stimuli Intraneural microstimulation Occasionally Yes Secondary sensations Allokinesis (itchy Hyperalgesia skin) Psychogenic modification Pronounced Present Counterstimuli Scratching, pain, Tactile stimuli, cooling cooling Neurophysiology Primary afferent neurones C-- and A.delta.-fibres C-- and A.delta.-fibres Flare size Large Small Spinal pathway Anterolateral funiculus Anterolateral funiculus Protective reflexes Scratching, sneezing Flexion, guarding Autonomic reflexes Yes Yes Pharmacology Capsaicin sensitivity Yes Chemogenic pain; yes NSAID sensitivity Probably not Yes Morphine sensinvity No Yes ______________________________________ Abbreviation: NSAID, nonsteroidal antiinflammatory drugs.
Experimental focal itch stimuli are surrounded by a halo of seemingly unaffected tissue where light tactile stimuli are capable of eliciting itch-like sensations. The term itchy skin or allokinesis has been coined for these secondary sensations that are reminiscent of the features of secondary hyperalgesia evolving around a painful focus. A crucial observation is that itch and pain usually do not coexist in the same skin region and a mild noxious stimulus such as scratching is in fact the singly most effective way to abolish itch. This abolition of itch can be prolonged producing an `antipruritic state`. Although mild scratch is often not painful, microneurographic recordings from humans have directly determined that such stimuli are among the most effective ways to excite cutaneous unmyelinated nociceptive afferents. (See, for example:
Shelly, W. B. and Arthur, R. P. (1957) Arch. Dermatol. 76, 296-323; PA1 Simone, D. A. et al. (1987) Somatosens. Res. 5, 81-92; PA1 Graham, D. T. , Goodell, H. and Wolff, H. G. (1951) J. Clin. Invest. 30, 37-49; PA1 Simone, D. A., Alreja, M. and LaMotte, R. H. (1991) Somatosens, Mot. Res. 8, 271-279; PA1 Torebjork, E (1985) Philos. Trans. R. Soc. London Ser. B 308, 227-234; and PA1 Vallbo, A. B., Hagbarth, K. E., Torebjork, H. E. and Wallin, B. G. (1979) Physiol. Rev. 59, 919-957). PA1 A is a single chemical bond (-), --(CH.sub.2).sub.q, CH(CH.sub.3)-- or --X(CH.sub.2).sub.n PA1 Ar is an aromatic, hetero-aromatic, bicyclic-aromatic, tricyclic-aromatic group or diphenyl methyl each of which may be unsubstituted or substituted with a member selected from the group consisting of H, halo, trifluoromethyl, nitro, C.sub.1 -C.sub.3 -alkoxy, hydroxy, azido, C.sub.1 -C.sub.3 -alkyl, methanesulfonyl, cyano, amino, C.sub.1 -C.sub.3 -alkoxycarbonyl, C.sub.1 -C.sub.3 -alkanoyloxy, and C.sub.1 -C.sub.3 -carboxacylamino of the formula --NHC(O)R.sub.7 PA1 R.sub.1 and R.sub.2 are independently H, C.sub.1 -C.sub.3 -alkyl or allyl; PA1 R.sub.1 and R.sub.2, taken together with the nitrogen to which they are bonded, complete a ring selected from the group consisting of azetidinyl, pyrrolidinyl, 3-hydroxypyrrolidinyl, 3-fluoropyrrolidinyl, morpholinyl, piperidinyl, and 3,4-dehydropiperidinyl; PA1 R.sub.3, R.sub.4, R.sub.5, R.sub.6 are independently H, hydroxy, OR.sub.8 or OC(.dbd.O)R.sub.9 ; PA1 R.sub.5 and R.sub.6 taken together may form the group --E--CH.sub.2 --CH.sub.2 --E--; PA1 R.sub.5 and R.sub.6 taken together form a ring ##STR2## where Z is selected from the group consisting of oxygen (--O--), NR.sub.10, sulfur (--S--), sulfinyl (--S(O)--), and sulfonyl (--S(O).sub.2 --); PA1 E is N.about.OH, N.about.OC(O)CH.sub.3, O, S, with the proviso that when E is bivalent sulfur or oxygen, R.sub.5 and R.sub.6 cannot both be hydrogen; PA1 R.sub.8 is C.sub.1 -C.sub.3 -alkyl; PA1 R.sub.9 is H or C.sub.1 -C.sub.3 -alkyl; and PA1 R.sub.10 is H, or C.sub.1 -C.sub.3 -alkyl. PA1 Ar denotes an aromatic or hetero-aromatic group such as pyridine, thiophene, a bicyclic-aromatic group such as naphthalenes, benzofurans, benzothiophines, a tricyclic-aromatic group such as anthracenes and fluorenes; and halo denotes F, Cl, Br or I. PA1 A is ##STR4## or, --CH.sub.2 CH.sub.2 -- provided that in Formula A, when n is 1, A may also be --O-- or --S--; B, C and D are independently selected from the group consisting of H, OH, OCOR.sup.5, OCH.sub.2 CH.sub.2 OR.sup.5, OR.sup.6, R.sup.6, CH.sub.2 OR.sup.6, CH.sub.2 COR.sup.7, Cl, F, Br, I, NH.sub.2, NHR.sup.8, NR.sup.8 R.sup.9, SH, SR.sup.6, CH.sub.2 SR.sup.6 and OC(S)N(CH.sub.3).sub.2 ; or PA1 two of B, C and D when on adjacent carbon atoms taken together form a fused benzo ring; PA1 X and Y are independently selected from the group consisting of H, OCH.sub.3, Cl, F, Br, I, NO.sub.2, CF.sub.3, CN, SO.sub.2 R.sup.10, and SO.sub.2 CF.sub.3 ; or PA1 X and Y taken together with the benzene ring form ##STR5## R and R.sup.1 independently are selected from the group consisting of H, and alkyl of 1 to 3 carbon atoms; PA1 R.sup.2 is H; alkyl of 1 to 6 carbon atoms; CH.sub.2 CF.sub.3 ; alkenylmethyl of 3 to 6 carbon atoms; hydroxyalkenylmethyl of 2 to 5 carbon atoms; cycloalkyl of 3 to 6 carbon atoms; cyclopropylmethyl; cyclobutylmethyl, or phenylalkyl of 7 to 9 carbon atoms; or R.sup.2 can be taken together with R.sup.1 and the nitrogen to which they are attached to be 1-azetidinyl; 1-pyrrolidinyl optionally substituted at the 3-position by OH, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms or alkanoyloxy of 1 to 3 carbon atoms; 1-piperazinyl optionally substituted at the 4-position by alkyl of 1 to 3 carbon atoms; 1-morpholino; 2,5-dihydro-1H-pyrrol-1-yl; 3-azabicyclo[3.1.0]hexan-3-yl; or 3-azabicyclo[3.2.0]heptan-3-yl; PA1 R.sup.3 is H, but if n is 1 and A is CH.sub.2, R.sup.3 may also be CH.sub.3, CH.sub.2 OH, CHO, or COR.sup.11 ; PA1 R.sup.4 is H, alkyl of 1 to 6 carbon atoms, --CH.sub.2 OH--, CHO, or COR.sup.12 ; PA1 R.sup.5 is alkyl of 1 to 6 carbon atoms, phenyl, or mono-substituted phenyl; PA1 R.sup.6, R.sup.8, R.sup.9, R.sup.10 and R.sup.13 are independently an alkyl group of 1 to 3 carbon atoms; and PA1 R.sup.7, R.sup.11 and R.sup.12 independently are selected from the group consisting of H, OH, OR.sup.13, NHR.sup.13, and NR.sub.2.sup.13 ; or PA1 a stable N-oxide or a pharmaceutically acceptable salt thereof. PA1 A is --CH.sub.2 --, --O--, or --S--; PA1 B is OH, OCOR.sup.5, OCH.sub.2 CH.sub.2 OR.sup.5, OR.sup.6, CH.sub.2 OR.sup.6, or CH.sub.2 COR.sup.7 ; PA1 C is H, OH, or OR.sup.6 ; and PA1 R.sup.1 and R.sup.2 independently are selected from H or alkyl of 1 to 3 carbon atoms or are taken together with the nitrogen to which they are attached to form the group 1-azetidinyl, 1-pyrrolidinyl, 1-(2,5-dihydro-1H-pyrrolyl) or 1-piperidinyl. PA1 R is unsubstituted phenyl or phenyl substituted with one to three substituents selected from the group consisting of halogen, C.sub.1-6 alkyl, hydroxy, --O--CO--NH.sub.2, --O--CO--NHalkyl, --O--CO--N(alkyl).sub.2, C.sub.1-6 alkoxy, trifluoromethyl, C.sub.1-4 -alkoxy-C.sub.1-4 alkyloxy, carboxy-C.sub.1-4 alkyloxy, nitrile, nitro and amino; or mono or dialkyl amino, amide, sulfonamide, carboxamide; or mono or disubstituted carboxamide, ureido; or mono and di-alkylsubstituted ureido; or PA1 R represents an alkyl or cycloalkyl group having up to 7 carbon atoms. The cycloalkyl moiety, where present, can be optionally substituted by one or more substituents selected from the group consisting of from hydroxy, amino, amidino, guanidino, aminocarbonyl, carboxy, C.sub.1-6 alkoxy, (C.sub.1-6 alkoxy)carbonyl, (C.sub.3-6 alkenyloxy)carbonyl, (C.sub.3-6 alkynyloxy)carbonyl, C.sub.1-6 alkanoyloxy, C.sub.1-6 alkylsulfide, C.sub.1-6 alkylsulfoxide, C.sub.1-6 alkylsulfone, C.sub.1-6 (monoalkylamino)carbonyl, C.sub.1-6 acylamino, C.sub.1-6 acylmethylamino and C.sub.1-6 monoalkylamino; or PA1 R represents the group --D--R.sup.8 in which D represents a single bond, --CH.sub.2 --, --CH(CH.sub.3)--, --CH.sub.2 O--, --CH(CH.sub.3)O--, --CH.sub.2 S--, --CH(CH.sub.3)S--, --CH.sub.2 NH-- or --CH(CH.sub.3)NH-- and R.sup.8 represents a 4-6 membered heterocyclic ring containing up to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, the heterocyclic ring optionally being substituted on nitrogen or sulfur by oxygen or on nitrogen by hydroxy or C.sub.1-3 alkyl and/or the ring optionally being substituted on carbon by one or more substituents selected from the group consisting of amino, hydroxy, thio (and their tautomers), cyano, halogen, C.sub.1-3 alkoxy, C.sub.1-3 monoalkylamino, C.sub.1-3 acylamino, C.sub.1-3 acylmethylamino, and C.sub.1-3 alkylthio; PA1 R.sup.1 and R.sup.2 are independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.3-5 alkenyl, C.sub.3-5 alkynyl, and C.sub.4-7 cycloalkylallyl group; or R.sup.2 can be taken together with R.sup.1 and the nitrogen to which they are attached to form a heterocyclic ring which may optionally contain a further heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur (i.e. 1-azetidinyl; 1-pyrrolidinyl optionally substituted at the 3-position by OH, --CH.sub.2 OH, tri(C.sub.1 -C.sub.6 alkyl)silyloxy, acyloxy, C.sub.1-6 alkyl, C.sub.1-6 alkoxy or C.sub.1-6 alkanoyloxy; 1-piperazinyl optionally substituted at the 4-position by alkyl of 1 to 3 carbon atoms; 1-morpholino; 2,5-dihydro-1H-pyrrol-1-yl; 3-azabicyclo[3.1.0]hexan-3-yl; or 3-azabicyclo[3.2.0]heptan-3-yl); PA1 R.sup.3 represents hydrogen, C.sub.1-7 alkyl, --CH.sub.2 -phenyl or heterocyclic (the phenyl or heterocyclic substituted with one to three substituents selected from the group consisting of halo, C.sub.1-4 alkyl, C.sub.1-4 alkoxy and methoxycarbonyl; mono-, di- or tri-halomethyl; cyano; COR.sup.9 ; CH.dbd.NOR.sup.10 ; OR.sup.10 ; SR.sup.10 ; CH.sub.2 CN; CH.sub.2 OR.sup.10 ; CH.sub.2 SR.sup.10 ; CH.sub.2 S(O)R.sup.10 ; CH.sub.2 S(O).sub.2 R.sup.10 ; CH.sub.2 N(R.sup.10)R.sup.11 ; CH.sub.2 (R.sup.10)R.sup.11 ; CH.sub.2 OR.sup.10 OH; CH.sub.2 N(COR.sup.10)OH; CH.sub.2 NR.sup.10 COR.sup.11 ; CH.sub.2 NR.sup.10 S(O).sub.2 R.sup.11 ; or CH.sub.2 OCOR.sup.10, wherein R.sup.9 is hydrogen, hydroxy, amino, NHOH, NHOCH.sub.3, pyridylamino, NHN(CH.sub.3).sub.2, C.sub.1-4 alkoxy, benzyloxy, C.sub.1-4 alkylamino, di-C.sub.1-4 alkylamino, C.sub.1-4 alkyl or C.sub.1-4 alkylthio; R.sup.10 and R.sup.11 are each hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy or C.sub.7-11 phenylalkyl), or OR.sup.12, wherein R.sup.12 is hydrogen, C.sub.1-4 alkyl or a hydroxy protecting group; PA1 X represents --CO--, or --SO.sub.2 --; and PA1 Y represents a single bond (in this case, only one of R.sup.4 -R.sup.6 is attached), a tetrahedral carbon, --OC--, --SC--, --S(O)C--, --S(O).sub.2 C--, or --CH.sub.2 C--; and PA1 R.sup.4, R.sup.5, and R.sup.6 are independently selected from the group consisting of hydrogen, hydroxy, alkoxy, C.sub.1-4 alkylenedioxy, C.sub.1-8 cyclic and acyclic alkyl; substituted or unsubstituted carbocyclic aromatic or heterocyclic aromatic group (i.e. phenyl, naphthyl, biphenyl, indanyl, 1-tetralone-6-yl, furyl, thienyl, pyridyl, thiazolyl, benzofuryl or benzothienyl, substituted with one to three substituents selected from the group consisting of halo, cyano, --OCONH.sub.2, --OCONHalkyl, --OCON(alkyl).sub.2, --OCOalkyl, --NHCHO, --NHCOalkyl, ureido, --NHCONHalkyl, --NalkylCONHalkyl, --NHCON(alkyl).sub.2, --NalkylCON(alkyl).sub.2, --NHSO.sub.2 alkyl, --COalkyl, --CONH.sub.2, --CONHalkyl, --CON(alkyl).sub.2, --CH.sub.2 CONH.sub.2, --CH.sub.2 CONHalkyl, --CH.sub.2 CON(alkyl).sub.2, --OCH.sub.2 CONH.sub.2, --OCH.sub.2 CONHalkyl, --OCH.sub.2 CON(alkyl).sub.2, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, amino, hydroxy, nitro, trifluoromethyl, --SO.sub.2 alkyl, --SOalkyl, and mesyl; or R.sup.5 and R.sup.6 can together form the following structure ##STR8## wherein R.sup.13 and R.sup.14 are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, mono-, di- or tri-halomethyl, amino, --NHalkyl, --N(alkyl).sub.2, --NHCOalkyl, ureido, nitro, and methylenedioxy; and PA1 D represents --CH--, --O--, --S--, --NH, --CHCH.sub.2 --, --CH.dbd.CH--, --CH.sub.2 NH--, or --CH.sub.2 Nalkyl--. PA1 R.sub.3 is hydrogen, C.sub.1-6 alkyl or phenyl; or R.sub.3 together with R.sub.1 forms a --(CH.sub.2).sub.3 -- or --(CH.sub.2).sub.4 -- group; PA1 R.sub.4 is C.sub.1-6 alkyl, or phenyl; PA1 R.sub.5 is hydrogen, or together with R.sub.4 forms a C.sub.2-5 linear polymethylene group; PA1 R.sub.6 represents hydroxy, C.sub.1-6 alkyl, C.sub.1-6 hydroxyalkyl, C.sub.1-6 carboxyalkyl, phenyl, oxo, amino, carboxy, amido, --COR.sub.13, --CO.sub.2 R.sub.13 or --COCO.sub.2 R.sub.13 (where R.sub.13 represents a hydrogen atom or an unsubstituted or substituted C.sub.1-10 hydrocarbon moiety); --NRxCORx (where Rx represents C.sub.1-6 alkyl), optionally substituted ethylene; or R.sub.6 together with the E atom to which it is attached, forms a 5 or 6-membered ring containing one or more heteroatoms; R.sub.7 is hydrogen, or together with R.sub.6 forms an optionally substituted or unsubstituted single or fused aryl or heterocyclic ring, containing from 5 to 12 ring atoms and comprising up to four heteroatoms in the ring selected from the group consisting of oxygen, nitrogen and sulphur, which may be substituted with hydrogen, C.sub.1-6 alkyl, --CH.sub.2 OR.sub.14, halogen, hydroxy, C.sub.1-6 alkoxy, C.sub.1-6 alkoxycarbonyl, thiol, C.sub.1-6 alkylthio, --OCOR.sub.15, --NHCOR.sub.16, --NHSO.sub.2 R.sub.17 or --CH.sub.2 SO.sub.2 NR.sub.18 R.sub.19, PA1 in which each of R.sub.14 to R.sub.19 is independently hydrogen, C.sub.1-6 alkyl, aryl or aralkyl, PA1 A is aryl or heteroaryl ring, optionally mono or disubstituted with C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.1-6 haloalkyl, C.sub.2-6 haloalkenyl, C.sub.2-6 haloalkynyl, aryl, aralkyl, hydroxy, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, thiol, C.sub.1-6 alkylthio, C.sub.1-6 haloalkylthio, halogen, nitro, cyano, carboxy, aryloxy, aralkoxycarbonyl, carbamoyl, sulfonyl or sulfamoyl; PA1 E represents methylene, sulphur, oxygen or an imino; PA1 R.sub.8 is hydrogen or C.sub.1-6 alkyl; and PA1 R.sub.9 is hydrogen or together with R.sub.8 may form the group --(CRaRa)m--C(.dbd.Y)-- wherein Ra is hydrogen or C.sub.1-6 alkyl having up to a maximum of 3 alkyl groups; PA1 m is 1, 2, or 3; and PA1 Y represents two hydrogens or oxygen. PA1 R.sup.1 represents an allyl group having 1-5 carbon atoms, a cycloalkylalkyl group having 4-7 carbon atoms, a cycloalkenylalkyl group having 5-7 carbon atoms, an aryl group having 6-12 carbon atoms, an aralkyl group having 7-13 carbon atoms, an alkenyl group having 4-7 carbon atoms, an allyl group, a furan-2-ylalkyl group having 1-5 carbon atoms, or a thiophen-2-ylalkyl group having 1-5 carbon atoms; PA1 R.sup.2 represents a hydrogen atom, a hydroxy group, a nitro group, an alkanoyloxy group having 1-5 carbon atoms, an alkoxy group having 1-5 carbon atoms, an alkyl group having 1-5 carbon atoms, or --NR.sup.9 R.sup.10 wherein R.sup.9 represents a hydrogen atom or an alkyl group having 1-5 carbon atoms, and R.sup.10 represents a hydrogen atom; an alkyl group having 1-5 carbon atoms, or --C(.dbd.O)R.sup.11 wherein R.sup.11 represents a hydrogen atom, a phenyl group or an alkyl group having 1-5 carbon atoms; PA1 R.sup.3 represents a hydrogen atom, a hydroxy group, an alkanoyloxy group having 1-5 carbon atoms, or an alkoxy group having 1-5 carbon atoms; PA1 A represents --XC(.dbd.Y)--, --XC(.dbd.Y)Z--, --X--, --XSO.sub.2 --, or --OC(OR.sup.4)R.sub.4 -- (where, X, Y and Z each independently represent NR.sup.4, S or O wherein R.sup.4 represents a hydrogen atom, a straight-chain or branched chain alkyl group having 1-5 carbon atoms or an aryl group having 6-12 carbon atoms, and wherein R.sup.4 may be identical or different; PA1 B represents a valence bond, a straight-chain or branched chain alkylene group having 1-14 carbon atoms (which may be substituted with at least one substituent selected from the group consisting of an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, a hydroxy group, fluorine, chlorine, bromine, iodine, an amino group, a nitro group, a cyano group, a trifluoromethyl group and a phenoxy group, and wherein 1 to 3 methylene groups may be replaced with carbonyl groups), an acyclic unsaturated hydrocarbon containing from 1 to 3 double bonds and/or triple bonds and having 2-14 carbon atoms (which may be substituted with at least one substituent group selected from the group consisting of an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, a hydroxy group, fluorine, chlorine, bromine, iodine, an amino group, a nitro group, a cyano group, a trifluoromethyl group and a phenoxy group, and wherein from 1 to 3 methylene groups may be replaced with carbonyl groups), or a straight-chain or branched chain saturated or unsaturated hydrocarbon group containing from 1 to 5 thioether, ether and/or amino bonds and having 1-14 carbon atoms (wherein hetero atoms are not bonded directly to A, and 1 to 3 methylene groups may be replaced with carbonyl groups); PA1 R.sup.5 represents a hydrogen atom or an organic group (which may be substituted with at least one or more substituent groups selected from the group consisting of an alkyl group having 1-5 carbon atoms, an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, a hydroxy group, fluorine, chlorine, bromine, iodine, an amino group, a nitro group, a cyano group, an isothiocyanate group, a trifluoromethyl group and a methylenedioxy group); or PA1 R.sub.5 is ##STR11## wherein Q is N, O or S; PA1 R.sup.6 represents a hydrogen atom; PA1 R.sup.7 represents a hydrogen atom, a hydroxy group, an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, or R.sup.6 and R.sup.7 together represent --O--, --CH.sub.2 -- or --S--; PA1 R.sup.8 represents a hydrogen atom, an alkyl group having 1-5 carbon atoms, or an alkanoyl group having 1-5 carbon atoms. The general formula (V) includes the (+) form, (-) form and (.+-.) form of compounds. PA1 R.sup.1 is an alkyl group having 1-5 carbon atoms, a cycloalkylmethyl group having 4-7 carbon atoms, a cycloalkenylmethyl group having 5-7 carbon atoms, a phenylalkyl group having 7-13 carbon atoms, an alkenyl group having 4-7 carbon atoms, an allyl group, a furan-2-yl-alkyl group having 1-5 carbon atoms or a thiophen-2-yl-alkyl group having 1-5 carbon atoms, while particularly preferred compounds are those wherein R.sup.1 is methyl, ethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopentenylmethyl, cyclohexenylmethyl, benzyl, phenethyl, trans-2-butenyl, 2-methyl-2-butenyl, allyl, furan-2-yl-methyl or thiophen-2-yl-methyl groups; PA1 R.sup.2 is hydrogen, hydroxy, nitro, acetoxy, methoxy, methyl, ethyl, propyl, amino, dimethylamino, acetylamino or benzoylamino groups, while particularly prefered compounds are those wherein R.sup.2 is hydrogen, hydroxy, nitro, acetoxy, methyl or dimethylamino groups; PA1 R.sup.3 is hydrogen, hydroxy, acetoxy or methoxy; PA1 A is --NR.sup.4 C(.dbd.O--, --NR.sup.4 C(.dbd.S)--, --NR.sup.4 C(.dbd.O)O--, --NR.sup.4 C(.dbd.O)NR.sup.4 --, --NR.sup.4 C(.dbd.S)NR.sup.4 --, --NR.sup.4 C(.dbd.O)S--, --OC(.dbd.O)--, --OC(.dbd.O)O--, --SC(.dbd.O)--, --NR.sup.4 --, --O--, --NR.sup.4 SO.sub.2 -- or --OSO.sub.2 --, while particularly preferred compounds are those wherein R.sup.3 is --NR.sup.4 C(.dbd.O)--, --NR.sup.4 C(.dbd.S)--, --NR.sup.4 C(.dbd.O)O--, --NR.sup.4 C(.dbd.O)NR.sup.4 --, --NR.sup.4 C(.dbd.S)NR.sup.4 -- or --NR.sub.4 SO.sub.2 --; PA1 R.sup.4 is hydrogen, a straight-chain or branched alkyl group having 1-5 carbon atoms or a phenyl group, while particularly particularly preferred compounds are those wherein R.sup.4 is a straight-chain or branched alkyl group having 1-5 carbon atoms, particularly methyl, ethyl, propyl, isopropyl, butyl and isobutyl groups; or PA1 R.sup.4 is ##STR12## wherein Q is N, O or S; PA1 B is --(CH.sub.2).sub.n -- (n=0-6), --(CH.sub.2).sub.n --C(.dbd.O)-- (n=1-4), --CH.dbd.CH--(CH.sub.2).sub.n -- (n=0-4), --C.tbd.C--(CH.sub.2).sub.n -- (n=0-4), --CH.sub.2 O--, --CH.sub.2 --S--, --CH.sub.2 --O--(CH.sub.2).sub.2 --O--(CH.sub.2).sub.2 --, --CH.sub.2 --O--CH.sub.2 --NH--CH.sub.2 --O--CH.sub.2 -- or --CH.sub.2 --O--CH.sub.2 --S--CH.sub.2 --O--CH.sub.2 --, while particularly preferred compounds are those wherein B is --(CH.sub.2).sub.n -- (n=0-6), --CH.dbd.CH(CH.sub.2).sub.n -- (n=0-4), --C.tbd.C--(CH.sub.2).sub.n -- (n=0-4), --CH.sub.2 --O-- or --CH.sub.2 --S--; PA1 R.sup.5 is hydrogen or an organic group having the basic skeleton indicated in (Formula V-1) (which may be substituted with at least one or more substituent groups selected from the group consisting of an alkyl group having 1-5 carbon atoms, an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, a hydroxy group, fluorine, chlorine, bromine, an amino group, a nitro group, a cyano group, an isothiocyanate group and a trifluoromethyl group), while particularly preferred compounds are those wherein R.sup.5 is hydrogen, phenyl, 3,4dichlorophenyl, 4-chlorophenyl, 3-chlorophenyl, 3,4-difluorophenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 4bromophonyl, 3-bromophenyl, 2-bromophenyl, 4-nitrophenyl, 3-nitrophenyl, 2-nitrophenyl, 4-trifuoromethylphenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-mothoxy, 3-furanyl, 2-furanyl, 3-thienyl, 2-thienyl, cyclopentyl or cyclohexyl groups.
Physiologically, there is evidence that substance P released from nociceptor terminals can cause the release of histamine from mast cells. Activation of mast cells, with release of the pruritogen histamine, occurs in immediate type hypersensitivity diseases, such as anaphylactic reactions and urticaria. Urticarial eruptions are distinctly pruritic and can involve any portion of the body, and have a variety of causes beyond hypersensitivity, including physical stimuli such as cold, solar radiation, exercise and mechanical irritation. Other causes of prutitus include: chiggers, the larval form of which secretes substance that creates a red papule that itches intensely; secondary hyperparathyroidism associated with chronic renal failure; cutaneous larva migrans, caused by burrowing larvae of animal hookworms; dermal myiasis, caused by maggots of the horse botfly, which can afflict horseback riders; onchocerciasis ("river blindness") caused by filarial nematodes; pediculosis, caused by lice infestations; enterobiasis (pinworm) infestations, which afflict about 40 million Americans, particularly school children; schistosome dermatitis (swimmer's itch); psoriasis; poison ivy, and asteatotic eczema ("winter itch"). The role of histamine or other endogenous pruritogens in mediating itch associated with these and other pruritic conditions, such as atopic dermatitis, its not yet well established. For atopic dermatitis, in particular, it appears that itch is not inhibited by antihistamines, but by cyclosporin A, a drug which inhibits the production of cytokines which have been proposed as potential pruritogens.
Current therapies for the treatment of itch include a variety of topical and systemic agents, such as steroids, antihistamines, and some psychotherapeutic tricyclic compounds, such as doxepin hydrochloride. Many such agents are listed in PDR Generics (see Second Edition, 1996, p. cv for a listing of said agents). The limitations of these agents are well known to medical practitioners, and are summarized in the "Warnings" and "Precautions" sections for the individual agents listed in PDR Generics. In particular, the lack of complete efficacy of antihistamines is well known, but antihistamines are frequently used in dermatology to treat prutitus due to urticaria, atopic dermatitis, contact dermatitis, psoriasis, and a variety of other conditions. Although sedation has been a frequent side effect of conventional systemically administered antihistamines, a new generation of antihistamines have been developed that are nonsedating, apparently due to their inability to cross the blood-brain barrier.
Intravenous administration of opiate analgesics, such as morphine and hydromorphone has been associated with pruritus, urticaria, other skin rashes, and wheal and flare over the vein being injected. These itch and itch-related reactions are believed to be due to a histamine-releasing property of these opiates, via mast cell degranulation. These opiates are thought to act upon the mu subtype of opiate receptor, but the possibility of interactions at the other principal opiate receptor subtypes (delta and kappa) cannot be excluded since these and other pruritogenic analgesics are not pure mu agonists. The cellular loci of the receptor type(s) mediating the itching effect is not known, although the mast cell is a possible candidate since opiates cause histamine release from these cells. However, some investigators have suggested that the frequent inability of antihistamines to block morphine-induced itching suggests a non-histaminergic mediation of opiate-induced itching--mechanism which could involve central opiate receptors. Although i.v. morphine only occasionally results in generalized itching (in about 1% of patients), prutitus is more prevalent in opiate analgesia with epidural (8.5%) or intraspinal (45.8%) administration. (See, for example: Bernstein et al., "Antipruritic Effect of an Opiate Antagonist, Naloxone Hydrochloride", The Journal of Investigative Dermatology, 78:82-83, 1982; and Ballantyne et al., "Itching after epidural and spinal opiates", Pain, 33: 149-160, 1988.)
To date, treatment with opiates has not only proven useless in the treatment of itch, but appears to exacerbate itch in mammals. The consistent findings from human studies indicate that whether by central or peripheral mechanisms, opiates appear to promote rather than prevent itching, and that opiate antagonists have antipuritic activity.
Human clinical studies have generally shown that opiates cause itching and there is evidence that these effects can be reproduced in animal models, where itching sensations per se cannot be reported, but scratching behavior can be observed. (See, for example: Thomas et al., "Microinjection of morphine into the rat medullary dorsal horn produces a dose-dependent increase in facial-scratching", Brain Research, 695: 267-270, 1996; Thomas et al., "Effects of central administration of opioids on facial scratching in monkeys", Brain Res., 585: 315-317, 1992; and Thomas et al., "The medullary dorsal horn: A site of action of opioids in producing facial scratching in monkeys", Anesthesiology, 79: 548-554, 1993).
We have now discovered that certain kappa agonists, which are substantially devoid of central nervous system effects, possess anti-pruritic activity in addition to antihyperalgesic activity. Accordingly, the present invention also provides safe and effective compositions for the prevention and treatment of pruritus.
Compounds having kappa opioid agonist activity are disclosed in the following references all of which are incorporated herein by reference:
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EPA 0 260 555 PA0 (.+-.)-N-[2-(N,N'-dimethylamino)cyclohexyl]-N-methyl-2-(4-trifluoromethylph enyl)acetamide; PA0 (.+-.)-N-[2-(N',N'-dimethylamino)cyclohexyl]-N-propyl-2-(3-methoxyphenyl)ac etamide; PA0 (.+-.)-N-[2-(N',N'-dimethylamino)cyclohexyl]-N-methyl-2-(4-azidopbenyl)acet amide; PA0 (.+-.)-N-[2-(N',N'-dimethylamino)cyclohexyl]-N-methyl-2-(3,4-dichlorophenyl )acetamide; PA0 (.+-.)-N-[2-(N',N'-dimethylamino)cyclohexyl]-N-methyl-2-(4-methoxyphenyl)ac etamide; PA0 (.+-.)-N-[2-(N',N'-dimethylamino)cyclohexyl]-N-methyl-2-(2-naphthyl)acetami de; PA0 (.+-.)-N-[2-(N-cyclopropyl-N-methylamino)cyclohexyl]-2-(4-azidophenyl)aceta mide; PA0 (.+-.)-N-(2-(3-acetoxy-1-pyrrolidinyl)cyclohexyl]-N-methyl-2-(3,4-dichlorop henyl)acetamide; PA0 (.+-.)-N-[2-(N-pyrrolidinyl)cyclohexyl]-N-methyl-2-(3,4-dichlorophenyl)acet amide; PA0 (.+-.)-N-[2-(3-hydroxypyrrolidinyl)cyclohexyl]-N-methyl-2-(3,4-dichlorophen yl)acetamide; PA0 (.+-.)-N-[2-[N'-(3-hydroxy-1-azetidinyl]cyclohexyl]methyl-2-(3,4-dichloroph enyl)acetamide; PA0 (.+-.)-N-[2-(N',N'-diethylamino)cyclohexyl]-N-methyl-2-(3,4-dichlorophenyl) acetamide; PA0 (.+-.)-N-[2-(N'-pyrrolidinyl)cyclohexyl]-N-methyl-2-(3,4-dichlorophenyl)pro pionamide; PA0 (.+-.)-N-[2-(4-methyl-1-piperazinylcyclopentyl]-2-(3,4-dichlorophenyl)aceta mide; PA0 (.+-.)-N-[2-(N,N-dimethylamino)cyclohexyl]-2-(3,4-dichlorophenyl)acetamide; PA0 (.+-.)-3,4-dichloro-N-methyl-N-[8-(1-pyrrolidinyl)-1,4-dioxaspiro[4.5]dec-7 -yl]-benzeneacetamide; PA0 (.+-.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1,4dioxaspiro[4.5]dec-8- yl]-benzeneacetamide; PA0 (.+-.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1,4-dioxaspiro[4.5]dec-6 -yl]-benzeneacetamide; PA0 (.+-.)-4-bromo-N-methyl-N-[7-(1-pyrrolidinyl)-1,4-dioxaspiro[4.5]dec.8.yl]- benzeneacetamide; PA0 (.+-.)-3.fluoro-N-ethyl-N-[7-(1-azetidinyl)-1,4-dioxaspiro[4.5]dec-8-yl]ben zeneacetamide; PA0 (.+-.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1,4-dioxaspiro[4.4]-non- 8-yl)-benzeneacetamide; PA0 (.+-.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1,4-dioxaspiro[4.6]-unde c-8-yl]-benzeneacetamide; PA0 (.+-.)-3,4-dichloro-N-methyl-N-[8-(1-pyrrolidinyl)-1,4-dioxaspiro[4.6]-unde c-7-yl]-benzeneacetamide; PA0 (.+-.)-3,4-dichloro-N-methyl-N-[9-(1-pyrrolidinyl)-1,4-dioxaspiro[4.6]-unde c-8-yl]-benzeneacetamide; PA0 (.+-.)-3,4-dichloro-N-[4methoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methylbenze acetamide; PA0 (.+-.)-3,4-dichloro-N-[5-methoxy-2-(1-pyrrolidinyilcyclohexyl]-N-methylbenz eneacetamide; PA0 (.+-.)-3,4-dichloro-N-methyl-N-[4-oxo-2-(1-pyrrolidinyl)cyclohexyl]-benzene acetamide; PA0 (.+-.)-4-bromo-N-methyl-N-[2-(N',N'-dimethylamino)4-oxo-cyclohexyl]benzenea cetamide; PA0 (.+-.)-N-[4-acetyloxy-2-(1-pyrrolidinyl)cyclohexyl]-3,4-dichloro-N-methylbe nzeneaceamide; PA0 (.+-.)-N-[4-acetyloxy-2-aminocyclohexyl]-3,4-difluoro-N-methylbenzeneacetar nide; PA0 (.+-.)-3,4-dichloro-N-[5-(hydroxyimino)-2-(1-pyrrolidinyl)cyclohexyl]-N-met hylbenzeneacetamide; PA0 (.+-.)-3,4-dichloro-N-[4,4-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methyl benzeneacetamide which can also be named: PA0 (.+-.)-3,4-dichloro-N-methyl-N-[4oxo-2-(1-pyrrolidinyl)cyclohexyl]benzeneac etamide, dimethyl ketal; PA0 (.+-.)-3,4-dichloro-N-[5,5-diethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methylb enzeneacetamide; PA0 (.+-.)-(1.alpha.,2.beta.)-3,4-dichloro-N-[4,4-dimethoxy-2-(1-pyrrolidinyl)c yclohexyl]-N-methyl benzeneacetamide; PA0 (.+-.)-4-trifluoromethyl-N-[4,4-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-m ethylbenzeneacetamides; PA0 (.+-.)-3-trifluoromethyl-N-[4,4-diethoxy-2-(1-pyrrolidinyl)-cyclohexyl]-N-m ethylbenzeneacetamide; PA0 (.+-.)-3-hydroxy-4-methyl-N-[4,4-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N- methylbenzeneacetamide; PA0 (.+-.)-4-methanesulfonyl-N-[4,4-dimethoxy-2-(1-piperidinyl)-cyclohexyl]-N-m ethylbenzamide; PA0 (.+-.)-4-acetyloxy-N-[4,4-dimethoxy-2-(1-pyrrolidinyl)-cyclohexyl-N-methylb enzeneacetamide; PA0 (.+-.)-N-[4,4-bis(methylthio)-2-(1-pyrrolidinyl)cyclohexyl]-3,4-dichloro-N- methylbenzeneacetamide; PA0 (.+-.)-N-[5,5-bis(ethylthio)-2-(1-pyrrolidinyl)cyclohexyl]-3,4-di-chloro-N- methylbenzeneacetamide; PA0 (.+-.)-3,4-dichloro-N-[4-methylthio-2-(1-pyrrolidinyl)cyclohexyl]-N-methylb enzeneacetamide; PA0 (.+-.)-3,4dichloro-N-[5-ethylthio-2-(1-pyrrolidinyl)cyclohexyl]-N-methylben zeneacetamide; PA0 (.+-.)-3,4-dichloro-N-[6-methylthio-2-(1-pyrrolidinyl)cycloheptyl]-N-methyl benzeneacetamide; PA0 (.+-.)-3,4-dichloro-N-[4-mercapto-2-(1-pyrrolidinyl)cyclohexyl]-N-methylben zeneacetamide; PA0 [1R-(1.beta.,2.beta.,4.beta.,5.beta.)]-N-[4,5-dimethoxy-2-(1-pyrrolidinyl)c yclohexyl]-N-methyl-4-benzofuranacetamide; PA0 [1S-(1.alpha.,2.beta.,4.beta.,5.beta.)]-N-[4,5-dimethoxy-2-(1-pyrrolidinyl) cyclohexyl]-N-methyl-4-benzofuranacetamide; PA0 [1R-(1.alpha.,2.beta.,4.alpha.,5.alpha.)]-N-[4,5-dimethoxy-2-(1-pyrrolidiny l)cyclohexyl]-N-methyl-4-benzofuranacetamide; PA0 [1S-(1.alpha.,2.beta.,4.alpha.,5.alpha.)]-N-[4,5-dimethoxy-2-(1-pyrrolidiny l)cyclohexyl]-N-methyl-4-benzofuranacetamide; PA0 [1R-(1.alpha.,2.beta.,4.beta.,5.beta.)]-N-[4,5-dimethoxy-2-(1-pyrrolidinyl) cyclohexyl]-N-methyl-benzo[b]thiophene-4-acetamide; PA0 [1S-(1.alpha.,2.beta.,4.beta.,5.beta.)]-N-[4,5-dimethoxy-2-(1-pyrrolidinyl) cyclohexyl]-N-methyl-benzo[b]thiophene-4-acetamide; PA0 [1R-(1.alpha.,2.beta.,4.alpha.,5.alpha.)]-N-[4,5-dimethoxy-2-(1-pyrrolidiny l)cyclohexyl]-N-methyl-benzo[b]thiophene-4-acetamide; PA0 [1S-(1.alpha.,2.beta.,4.alpha.,5.alpha.)]-N-[4,5-dimethoxy-2-(1-pyrrolidiny l)cyclohexyl]-N-methyl-benzo[b]thiophene-4-acetamide; PA0 [1R-(1.alpha.,2.beta.,4.beta.,5.beta.)]-N-[4,5-dimethoxy-2-(1-pyrrolidinyl) cyclohexyl]-N-methyl-1-naphthaleneacetamide; PA0 [1S-(1.alpha.,2.beta.,4.beta.,5.beta.)]-N-[4,5-dimethoxy-2-(1-pyrrolidinyl) cyclohexyl]-N-methyl-1-naphthaleneacetamide; PA0 [1R-(1.alpha.,2.beta.,4.alpha.,5.alpha.)]-N-[4,5-dimethoxy-2-(1-pyrrolidiny l)cyclohexyl]-N-methyl-1-naphthaleneacetamide; PA0 [1S-(1.alpha.,2.beta.,4.alpha.,5.alpha.)]-N-[4,5-dimethoxy-2-(1-pyrrolidiny l)cyclohexyl]-N-methyl-1-naphthaleneacetamide; PA0 [1R-(1.alpha.,2.beta.,4.beta.,5.beta.)]-3,4-dichloro-N-[4,5-dimethoxy-2-(1- pyrrolidinyl)cyclohexyl]-N-methybenzeneacetamide; PA0 [1S-(1.alpha.,2.beta.,4.beta.,5.beta.)]-3,4-dichloro-N-[4,5-dimethoxy-2-(1- pyrrolidinyl)cyclohexyl]-N-methybenzeneacetamide; PA0 [1R-(1.alpha.,2.beta.,4.alpha.,5.alpha.)]-3,4-dichloro-N-[4,5-diethoxy-2-(1 -pyrrolidinyl)cyclohexyl]-N-methybenzeneacetamide; PA0 [1S-(1.alpha.,2.beta.,4.alpha.,5.alpha.)]-3,4-dichloro-N-[4,5-dimethoxy-2-( 1-pyrrolidinyl)cyclohexyl]-N-methybenzeneacetamide; PA0 [1R-(1.alpha.,2.beta.,4.beta.,5.beta.)]-N-[4,5-dimethoxy-2-(1-pyrrolidinyl) cyclohexyl]-N-methyl-9H-fluorene-9-carboxamide; PA0 [1S-(1.alpha.,2.beta.,4.beta.,5.beta.)]-N-[4,5-dimethoxy-2-(1-pyrrolidinyl) cyclohexyl]-N-methyl-9H-fluorene-9-carboxamide; PA0 [1R-(1.alpha.,2.beta.,4.alpha.,5.alpha.)]-N-[4,5-dimethoxy-2-(1-pyrrolidiny l)cyclohexyl]-N-methyl-9H-fluorene-9-carboxamide; PA0 [1S-(1.alpha.,2.beta.,4.alpha.,5.alpha.)]-N-[4,5-dimethoxy-2-(1-pyrrolidiny l)cyclohexyl]-N-methyl-9H-fluorene-9-carboxamide; PA0 (.+-.)-(1.alpha.,2.beta.,4.beta.)-N-methyl-N-[4methoxy-2-(1-pyrrolidinyl)cy clohexyl]-4-benzofuranacetamide; PA0 (.+-.)-(1.alpha.,2.beta.,4.alpha.)-N-methyl-N-[4-methoxy-2-(1-pyrrolidinyl) cyclohexyl]-4-benzofuranacetamide; PA0 (.+-.)-(1.alpha.,2.beta.,5.beta.)-N-methyl-N-[5-methoxy-2-(1-pyrrolidinyl)c yclohexyl]-4-benzofuranacetamide; PA0 (.+-.)-(1.alpha.,2.beta.,5.alpha.)-N-methyl-N-[5-methoxy-2-(1-pyrrolidinyl) cyclohexyl]-4-benzofuranacetamide; PA0 (.+-.)-(1.alpha.,2.beta.,4.alpha.)-N-[4-methoxy-2-(1-pyrrolidinyl)cyclohexy l]-N-methyl-9H-fluorene-9-carboxamide; PA0 (.+-.)-(1.alpha.,2.beta.,5.beta.)-N-[5-methoxy-2-(1-pyrrolidinyl)cyclohexyl ]-N-methyl-9H-fluorene-9-carboxamide; PA0 (.+-.)-N-methyl-2-(1-naphthalenyloxy)-N-[2-(1-pyrrolidinyl)cyclohexyl]aceta mide; PA0 (.+-.)-N-methyl-2-(2-naphthalenyoxy)-N-[2-(1-pyrrolidinyl)cyclohexy]jacetam ide; PA0 (.+-.)-1,2dihydro-N-methyl-N-[2-(1-pyrrolidinyl)cylohexyl]-1-acenaphthylenc arboxamide, (isomer I, mixture of (1.alpha.,2.beta.) and (1.beta.,2.alpha.) forms); PA0 (.+-.)-1,2-dihydro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-1-acenaphthyle necarboxamide, (isomer II, mixture of (1.alpha.,2.beta.) and (1.beta.,2.alpha.) forms); PA0 (.+-.)-N-[4,5-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-1,2-dihydro-N-methyl- 1-acenaphthylenecarboxamide (isomer I, mixture of (1.alpha.,2.beta.,4.beta.,5.beta.) and (1.beta.,2.alpha.,4.alpha.,5.alpha. forms); PA0 (.+-.)-N-[4,5-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-1,2-dihydro-N-methyl- 1-acenaphthylenecarboxamide (isomer II, mixture of (1.alpha.,2.beta.,4.beta.,5.beta.) and (1.beta.,2.alpha.,4.alpha.,5.alpha. forms); PA0 (.+-.)-1,2-dihydro-N-[4-methoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methyl-1-ac enaphthylenecarboxamide (isomers I and II, mixtures of (1.alpha.,2.beta.,4.beta.) and (1.beta.,2.alpha.,4.alpha.) forms); PA0 (.+-.)-1,2-dihydro-N-[4-methoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methyl-1-ac enaphthylenecarboxamide (isomers I and II, mixtures of (1.beta.,2.alpha.,4.alpha.) and (1.alpha.,2.beta.,4.beta.) forms); PA0 (.+-.)-trans-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-9H-fluorene-9-carbox amide; PA0 (.+-.)-trans-1,3-dihydro-N-methyl-1-oxo-N-[2-(1pyrrolidinyl)cyclohexyl]-4-i sobenzofuranacetamide; PA0 (.+-.)-(1.alpha.,2.beta.,4.beta.,5.beta.)-N-[4,5-dimethoxy-2-(1-pyrrolidiny l)cyclohexyl]-1,3-dihydro-N-methyl-1-oxo-4-isobenzofuranacetamide; PA0 (.+-.)-(5.alpha.,7.alpha.,8.beta.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidin yl)-1-oxaspiro[4.5]dec-8-yl]benzeneacetamide; PA0 (.+-.)-(5.alpha.,7.alpha.,8.beta.)-bromo-N-methyl-N-[7-(1-pyrrolidinyl)-1-o xaspiro[4.5]dec-8-yl]benzeneacetamide; PA0 (.+-.)-(5.alpha.,7.alpha.,8.beta.)-4-methoxy-N-methyl-N-[7-(1-pyrrolidinyl) -1-oxaspiro[4.5]dec-8-yl]benzeneacetamide; PA0 (.+-.)-(5.alpha.,7.alpha.,8.beta.)-N-methyl-2-nitro-N-[7-(1-pyrrolidinyl)-1 -oxaspiro[4.5]dec-8-yl]benzeneacetamide; PA0 (.+-.)-(5.alpha.,7.alpha.,8.beta.)-N-methyl-3-nitro-N-[7-(1-pyrrolidinyl)-1 -oxaspiro[4.5]dec-8-yl]benzeneacetamide; PA0 (.+-.)-(5.alpha.,7.alpha.,8.beta.)-N-methyl-4-nitro-N-[7-(1-pyrrolidinyl)-1 -oxaspiro[4.5]dec-8-yl]benzeneacetamide; PA0 (.+-.)-(5.alpha.,7.alpha.,8.beta.)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspir o[4.5]dec-8-yl]-3-(trifluoromethyl)benzeneacetamide; PA0 (.+-.)-(5.alpha.,6.alpha.,7.beta.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidin yl)-1-oxaspiro[4.5]dec-6-yl]benzeneacetamide; PA0 (.+-.)-(5.alpha.,7.alpha.,8.beta.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidin yl)-1-thiaspiro[4.5]dec-8-yl]benzeneacetamide; PA0 (.+-.)-(5.alpha.,7.beta.,8.alpha.)-3,4-dichloro-N-methyl-N-[8-(1-pyrrolidin yl)-1-oxaspiro[4.5]dec-7-yl]benzeneacetamide; PA0 (.+-.)-(5.alpha.,7.alpha.,8.beta.)-3,4-dichloro-1,N-dimethyl-[7-(1-pyrrolid inyl)-1-azaspiro[4.5]dec-8-yl]benzeneacetamide; PA0 (.+-.)-(5.alpha.,7.alpha.,8.beta.)-4-bromo-N-methyl-N-[7-(1-pyrrolidinyl)-1 -azaspiro[4.5dec-8-yl]benzamide; PA0 (.+-.)-(5.alpha.,7.alpha.,8.beta.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidin yl)-1-thiaspiro[4.5]dec-8-yl]benzamide; PA0 (.+-.)-(5.alpha.,7.alpha.,8.beta.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidin yl)-1-thiaspiro[4.5]dec-8-yl]benzeneacetamide; PA0 (.+-.)-(5.alpha.,7.alpha.,8.beta.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidin yl)-1-thiaspiro[4.5]dec-8-yl]benzeneacetamide, 1-oxide; PA0 (.+-.)-(5.alpha.,7.alpha.,8.beta.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidin yl)-1-thiaspiro[4.5]dec-8-yl]benzeneacetamide, 1,1-dioxide; PA0 (.+-.)-(5.alpha.,7.alpha.,8.beta.)-N-methyl-N-[7-(1-pyrrolidinyl)-1-azaspir o[4.5]dec-8-yl]4-trifluoromethylbenzeneacetamide; PA0 (.+-.)-(5.alpha.,7.alpha.,8.beta.)-N-methyl-N-[8-(1-pyrrolidinyl)-1-thiaspi ro[4.5]dec-7-yl]-3-trifluoromethylbenzeneacetamide; PA0 [5R-(5.alpha.,7.alpha.,8.beta.)]-N-Methyl-[7-(1-pyrrolidinyl)-1-oxaspiro[4. 5]dec-8-yl]-1H-indene-3-acetamide; PA0 [5S-(5.alpha.,7.alpha.,8.beta.)]-N-Methyl-[7-(1-pyrrolidinyl)-1-oxaspiro[4. 5]dec-8-yl]-1H-indene-3-acetamide; PA0 [5R-(5.alpha.,7.beta.,8.alpha.)]-N-Methyl-[7-(1-pyrrolidinyl)-1-oxaspiro[4. 5]dec-8-yl]-1H-indene-3-acetamide; PA0 [5S-(5.alpha.,7.beta.,8.alpha.)]-N-Methyl-[7-(1-pyrrolidinyl)-1-oxaspiro[4. 5]dec-8-yl]-1H-indene-3-acetamide; PA0 [5R-(5.alpha.,7.alpha.,8.beta.)]-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[ 4.5]dec-8-yl]-1H-indole-3-acetamide; PA0 [5S-(5.alpha.,7.alpha.,8.beta.)]-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[ 4.5]dec-8-yl]-1H-indole-3-acetamide; PA0 [5R-(5.alpha.,7.beta.,8.alpha.)]-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[ 4.5]dec-8-yl]-1H-indole-3-acetamide; PA0 [5S-(5.alpha.,7.beta.,8.alpha.)]-N-Methyl-N-[7-(-pyrrolidinyl)-1-oxaspiro[4 .5]dec-8-yl]-1H-indole-3-acetamide; PA0 [5R-(5.alpha.,7.alpha.,8.beta.)]-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[ 4.5]dec-8-yl]-2-benzofuranacetamide; PA0 [5S-(5.alpha.,7.alpha.,8.beta.)]-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[ 4.5]dec-8-yl]-2-benzofuranacetamide; PA0 [5R-(5.alpha.,7.beta.,8.alpha.)]-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[ 4.5]dec-8-yl]-2-benzo[b]furanacetamide; PA0 [5S-(5.alpha.,7.beta.,8.alpha.)]-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[ 4.5]dec-8-yl]-2-benzo[b]furanacetamide; PA0 [5R-(5.alpha.,7.alpha.,8.beta.)]-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[ 4.5]dec-8-yl]-3-benzo[b]furanacetamide; PA0 [5S-(5.alpha.,7.alpha.,8.beta.)]-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[ 4.5]dec-8-yl]-3-benzo[b]furanacetamide; PA0 [5R-(5.alpha.,7.beta.,8.alpha.)]-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[ 4.5]dec-8-yl]-3-benzo[b]furanacetamide; PA0 [5S-(5.alpha.,7.beta.,8.alpha.)]-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[ 4.5]dec-8-yl]-3-benzo[b]furanacetamide; PA0 [5R-(5.alpha.,7.alpha.,8.beta.)]-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[ 4.5]dec-8-yl]-4-benzo[b]furanacetamide; PA0 [5S-(5.alpha.,7.alpha.,8.beta.)]-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[ 4.5]dec-8-yl]-4-benzo[b]furanacetamide; PA0 [5R-(5.alpha.,7.beta.,8.alpha.)]-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[ 4.5]dec-8-yl]4-benzo[b]furanacetamide; PA0 [5S-(5.alpha.,7.beta.,8.alpha.)]-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[ 4.5]dec-8-yl]-4-benzo[b]furanacetamide; PA0 [5R-(5.alpha.,7.alpha.,8.beta.)]-N-Methyl-N-7-(1-pyrrolidinyl)-1-oxaspiro[4 .5]dec-8-yl-4-benzo[b]thiophene-4-acetamide; PA0 [5S-(5.alpha.,7.alpha.,8.beta.)]-N-Methyl-N-7-(1-pyrrolidinyl)-1-oxaspiro[4 .5]dec-8-yl-4-benzo[b]thiophene-4-acetamide; PA0 [5R-(5.alpha.,7.beta.,8.alpha.)]-N-Methyl-N-7-(1-pyrrolidinyl)-1-oxaspiro[4 .5]dec-8-yl-4-benzo[b]thiophene-4-acetamide; PA0 [5S-(5.alpha.,7.beta.,8.alpha.)]-N-Methyl-N-7-(1-pyrrolidinyl)-1-oxaspiro[4 .5]dec-8-yl-4-benzo[b]thiophene-4-acetamide; PA0 (-)-(5.alpha.,7.alpha.,8.beta.)]-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[ 4.5]dec-8-yl]-4-benzo[b]furanacetamide; PA0 (-)-(5.alpha.,7.alpha.,8.beta.)]-N-7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8- yl-4-benzo[b]thiophene-4-acetamide; PA0 (.+-.)-(5.alpha.,6.alpha.,7.beta.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidin yl)-2-oxaspiro[4.5]dec-6-yl]benzeneacetamide; PA0 (.+-.)-(5.alpha.,6.alpha.,7.beta.)-3,4-dichloro-N-methyl-N-[6-(1-pyrrolidin yl)-2-oxaspiro[4.5]dec-7-yl]benzeneacetamide; and PA0 (.+-.)-(5.alpha.,7.alpha.,8.beta.)-3,4-dichloro-N-methyl-N-[8-(1-pyrrolidin yl)-2-oxaspiro[4.5]dec-7-yl]benzeneacetamide. PA0 (.+-.)trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-5-methoxy-1,2,3,4- tetrahydronaphth-1-yl]-benzeneacetamide hydrochloride or the methansulfonic acid salt; PA0 (.+-.)trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-1,2,3,4-tetrahydro naphth-1-yl]-benzeneacetamide hydrochloride; PA0 (.+-.)trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-6-methoxy-1,2,3,4- tetrahydronaphth-1-yl]-benzeneacetamide hydrochloride; PA0 (.+-.)trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-6-hydroxy-1,2,3,4- tetrahydronaphth-1-yl]-benzeneacetamide hydrochloride; PA0 (.+-.)-trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-1,2,3,4-tetrahydr onaphth-1-yl]-benzeneacetamide hydrochloride; PA0 (.+-.)trans-3,4-dichloro-N-methyl-N-[2,3-dihydro-2-(pyrrolidin-1-yl)-1H-ind en-1-yl]-benzeneacetamide hydrochloride; PA0 (.+-.)trans-3,4-dichloro-N-methyl-N-[3,4-dihydro-3-(pyrrolidin-1-yl)-2H-ben zopyran4-yl]-benzeneacetamide hydrochloride; PA0 (.+-.)trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-5-hydroxy-1,2,3,4- tetrahydronaphth-1-yl]-benzeneacetamide hydrochloride; PA0 (.+-.)trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-5-propionyloxy-1,2 ,3,4-tetrahydronaphth-1-yl]-benzeneacetamide hydrochloride; PA0 (.+-.)trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-5-benzoyloxy-1,2,3 ,4-tetrahydronaphth-1-yl]-benzeneacetamide hydrochloride; PA0 (.+-.)trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-6,7-dihydroxy-1,2, 3,4-tetrahydronaphth-1-yl]-benzeneacetamide hydrochloride; PA0 (.+-.)trans-N-methyl-N-[3,4-dihydro-3-(pyrrolidin-1-yl)-2H-benzopyran-4-yl] -benzeneacetamide hydrochloride; PA0 (.+-.)trans-3,4-dichloro-N-methyl-N-[3,4dihydro-8-methoxy-3-(pyrrolidin-1-y l)-2H-benzopyran-4yl]-benzeneacetamide hydrochloride; PA0 (.+-.)trans-3,4dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-5-(N,N-dimethylthio carbamoyloxy)-1,2,3,4-tetrahydronaphth-1-yl]-benzeneacetamide hydrochloride; PA0 (.+-.)trans-3,4dichloro-N-methyl-N-[2-(2,5-dihydro-1H-pyrrol-1-yl)-5-methox y-1,2,3,4-tetrahydronaphth-1-yl]-benzeneacetamide hydrochloride, and PA0 (.+-.)trans-3-nitro-N-methyl-N-[2,3-dihydro-2-(pyrrolidin-1-yl)-1H-inden-1- yl]-benzeneacetamide hydrochloride. PA0 N-methyl-N-{[1S]-1-phenyl-2-[(3S)-(3-hydroxypyrrolidin-1-yl)]ethyl}-2,2-dip henylacetamide hydrochloride, PA0 3,4dichloro-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]benzeneacetam ide hydrochloride, PA0 N-methyl-N-{[1S]-1-phenyl-2-[(3S)-(3-hydroxypyrrolidin-1-yl)]ethyl }-2-aminophenylacetamide hydrochloride, PA0 3,4-dichloro-N-methyl-N-[(1S)-1-isopropyl-2-(1-pyrrolidinyl)ethyl]benzeneac etamide hydrochloride, PA0 3,4-dichloro-N-methyl-N-[(1S)-1-(O-acetic acid-3-hydroxyphenyl)-2-(1-pyrrolidinyl)ethyl]benzeneacetamide hydrochloride, and PA0 N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]-2,2-diphenylacetamide hydrochloride PA0 (.+-.)1-(Pyrrolidin-1-yl)methyl-2-(3,4dichlorophenyl)-acetyl-4,4-dimethyl-1 ,2,3,4-tetrahydroisoquinoline; PA0 (.+-.)8-[(3,4-Dichlorophenyl)acetyl]-7-(1-pyrrolidinylmethyl)-1,4-dioxa-8-a za[4.5]spirodecane; PA0 (.+-.)Methyl 4-[3,4dichlorophenyl)acetyl]-3-(1-pyrrolidinylmethyl)-1-piperazinecarboxyl ate 1-[(3,4-Dichlorophenyl)acetyl]-2-[(3-oxo-1-pyrolidinyl)methyl]-piperidine; PA0 (.+-.)[S-(RR)]-(-)5-[(3,4-Dichlorophenyl)acetyl]-4,5,6,7-tetrahydro-4[(3-hy droxy-1-pyrolidinyl)methyl]furo[3,2-c]pyridine; PA0 (.+-.)[S-(RS)]-4-Acetyl-1-[(3,4-dichlorophenyl)acetyl]-2-[(3-hydroxy-1-pyro lidinyl)methyl]pyridine; PA0 (.+-.)2-[(3,4-Dichlorophenyl)acetyl]-1,2,3,4-tetrahydro-1-(1-pyrolidinyl)me thyl)-5-isoquinolinol; PA0 (.+-.)4-(Pyrolidin-1-yl)methyl-5-(3,4-dichlorophenyl)acetyl-4,5,6,7-tetrahy drothieno[3,2,c]pyridine; PA0 (.+-.)1-[(5,6-Dichloro-3-oxoindan-1-carbonyl)-2-pyrrolidin-1-ylmethyl)piper idine; PA0 (.+-.)2-(3,4-Dichlorophenyl)acetyl-3-(pyridin-1-yl)methyl-decahydroisoquino line; and PA0 (.+-.)1-(4-Trifluoromethylphenyl)acetyl-2-(3-hydroxypyrolidin-1-yl)methyl-4 ,4-dimethyl piperidine. PA0 17-cyclopropylmethyl-4,5.alpha.-epoxy-3,14.beta.-dihydroxy-6.beta.-(N-methy l-3-phenylpropionamido)morphinan; PA0 17-cyclopropylmethyl-4,5.alpha.-epoxy-3,14.beta.-dihydroxy-6.beta.-(N-methy l-trans-3-(3-furyl)acrylamido)morphinan; PA0 17-cyclopropylmethyl-4,5.alpha.-epoxy-3,14.beta.-dihydroxy-6.beta.-(N-methy l-trans-3-cyclohexylacrylamido)morphinan; PA0 17-cyclopropylmethyl-4,5.alpha.-epoxy-3,14.beta.-dihydroxy-6.beta.-(N-methy l-trans-3-(4-trifuoromethylphenyl)acrylamido)morphinan; PA0 17-cyclopropylmethyl-4,5.alpha.-epoxy-3,14.beta.-dihydroxy-6.beta.-(N-methy l-trans-3-(3-thiophenyl)acrylamido)morphinan; PA0 17-cyclopropylmethyl-4,5.alpha.-epoxy-3,14.beta.-dihydroxy-6.beta.-(N-methy l-trans-3-phenylacrylamido)morphinan; PA0 17-cyclopropylmethyl-4,5.alpha.-epoxy-3,14.beta.-dihydroxy-6.beta.-(N-methy l-trans-2-hexenamido)morphinan; and PA0 17-cyclopropylmethyl-4,5.alpha.-epoxy-3,14.beta.-dihydroxy-6.beta.-(N-methy l-phenylpropiolamido)morphinan.